Cardiovascular disease (CVD) is the leading cause of death among women. Researchers and clinicians that can work across disciplinary boundaries are needed to effectively understand, prevent, and reduce the burden of CVD. A focus on women and CVD is critical given the multiple sex-specific risk factors for and manifestations of CVD that remain incompletely understood. This renewal application for an NHLBI Mid-Career Investigator Award in Patient-Oriented Research seeks support for Dr. Rebecca Thurston, an investigator with a strong track record in interdisciplinary mentoring, training, and research in midlife women's cardiovascular health. The specific aims of this Project are to provide Dr. Thurston with the training, resources, and protected time to strengthen and amplify the public health impact of her NIH-supported research program by: (1) providing outstanding mentorship and support for young investigators from diverse fields to address questions of critical importance to women's cardiovascular health; (2) supporting training for Dr. Thurston and her trainees in (a) advanced analytic mediation methods and (b) select physiologic mechanisms (inflammation, epigenetics) highly relevant to the development of CVD in women; and (3) to leverage ongoing NIH RF1- supported research and to build upon the first phase of K24-supported research that demonstrated critical cross-sectional relations of menopausal symptoms (sleep problems, vasomotor symptoms) to carotid atherosclerosis midlife women, relations not explained by traditional CVD risk factors or by sex hormones. We will now (a) investigate how persistence of menopausal symptoms over time relate to carotid atherosclerosis and its progression and (b) consider key novel mechanistic (inflammatory, epigenetic) pathways that may critically link menopausal symptoms to CVD risk in women. Proposed mentoring and career development activities are highly integrated, with the mutually reinforcing goals of advancing trainee careers and enhancing Dr. Thurston's burgeoning program of research and training in women's cardiovascular health.